Brain tumors (BTs) are incurable, whether they start in the brain or spread there from other sites. Despite advances in surgical, radiation, pharmacologic, and gene therapies, survival with a BT remains dismal. Current therapies are limited by their inability to reach widely disseminated tumor cells that become dispersed within normal brain structures. Interestingly, the therapeutic property that is needed to overcome this major obstacle to effective treatment of BTs matches well with one of the better accepted attributes of neural stem cells (NSCs): an attraction for sites of pathology in the adult brain, including primary & metastatic cancer. If armed with a proper tumor-killing gene, NSCs (whether administered into the brain or into the bloodstream), that are drawn to cancers, will dramatically reduce tumor burden, and will track after even single migrating tumor cells. The NSCs perform this action without themselves becoming tumorigenic or augmenting the pre-existing tumor, and this can be assured by having NSCs express a suicide gene that can be activated and cause NSCs to die. The tumor homing phenomenon of NSCs was first revealed by researchers on this proposed team and, in fact, the central concepts presented here have since been extended to many other kinds of disease. In this proposal, we will use a number of authentic mouse models of primary BTs to pre-clinically test therapeutic NSCs. Human NSCs (hNSCs) will be derived from 3 distinct sources, with each having been proffered as therapeutic, but never having been compared head-to-head in treating tumors. Each of these hNSCs will be modified using two therapeutic genes: TRAIL, which is a protein that specifically kills tumor cells, but does not harm normal cells and tissues, and cytosine deaminase which converts a non-toxic chemical into a toxic chemotherapeutic. We expect our research to identify the best hNSC + therapeutic gene combination to advance for clinical trial in patients with BTs, following our obtaining regulatory approval for using hNSC therapy at the end of this project. Because immunocompatibility of the hNSCs with recipient patients is not a concern in BT therapy, a limited number of hNSC lines can be used for treating all prospective patients. Furthermore, BT treatment does not require long-term NSC survival and can be combined with commonly used BT therapies. Finally, NSCs can be imaged in patients and therefore monitored after administration. Developing this approach for treatment of BT patients offers an ideal setting and opportunity for achieving dramatic results from stem cell therapy, and the results of this project will likely be applicable to the treatment of other cancers.

Statement of Benefit to California:

Brain tumors (BTs) are incurable, whether they start in the brain or spread there from other sites. Despite advances in surgical, radiation, drug, & gene therapies, survival with a BT is extremely short, because current therapies are limited by their inability to reach tumor cells that spread widely to normal brain structures. Interestingly, the therapeutic property that is needed to overcome this major treatment obstacle matches well with one of the better accepted attributes of neural stem cells (NSCs): an attraction for sites of disease in the adult brain, including primary & metastatic cancer. If engineered to be armed with a tumor-killing gene, NSCs (whether administered into the brain or into the bloodstream), that are attracted to cancers, could dramatically reduce patient tumor burden, and track after even single migrating tumor cells, in a manner that has never been achieved. The NSCs would perform this action without themselves causing tumors or increasing growth of the patient’s tumor, and this would be assured by engineering the NSCs to self-destruct. The tumor homing phenomenon of NSCs was first revealed by researchers on this proposed team and, in fact, the central concepts presented here have since been extended to many other kinds of disease. In this proposal, we will use a number of authentic mouse models of primary BTs to test therapeutic NSCs before testing them in humans. Human NSCs (hNSCs) will be derived from 3 distinct sources, with each having been proposed as therapeutic, but never having been compared head-to-head in treating cancer. Each of these stem cells will be modified using two different therapeutic genes: TRAIL, a protein that specifically kills tumor cells, but does not harm normal cells and tissues, and cytosine deaminase, which converts a non-toxic chemical into a chemotherapy drug that kills the tumor. We expect our research to identify the best hNSC + therapeutic gene combination to advance for evaluation in clinical trials in patients with intracranial BTs, after we have performed all necessary animal safety testing and submitted a complete plan for review by the US FDA and NIH. Members of this proposed team have experience in bringing cancer therapies to clinical trial, hold the IP surrounding the use of stem cells against cancer, have begun discussions with the FDA and NIH, and have enlisted a GMP facility. Because immune system compatibility between donor and recipient of the hNSCs with the recipient is not a concern in BT therapy, a small number of donors could be used to produce genetically modified hNSCs to treat all prospective patients. Developing this approach for treatment of BTs offers an ideal setting and opportunity for achieving dramatic results from stem cell therapy, and accomplishing substantial improvements in quantity and quality of life for BT patients would no doubt increase California's worldwide visibility in offering the best possible medical care for cancer patients.

Review Summary:

The goal of this proposal is to develop a human allogeneic stem cell product that delivers cytotoxic gene products to glioblastoma multiforme (GBM), specifically recurrent GBM. Human neural stem cells (hNSCs) will be genetically modified using one of two therapeutic genes: TRAIL (a protein that is directly cytotoxic to tumor cells) or cytosine deaminase (CD), which can convert a pro-drug to an active chemotherapeutic agent. The foundation for the approach lies in published preclinical data showing that hNSCs migrate to tumors, and thus could provide local delivery of TRAIL or the active drug at the tumor site. The applicant team proposes to compare head to head, in three different preclinical models, safety and efficacy of the two therapeutic genes delivered by hNSCs from three different sources via two routes of administration. With the “best” candidate hNSCs, the team will then develop the chemistry, manufacturing and control (CMC) information and a clinical protocol for a phase I study which are required to file an Investigational New Drug (IND) application.
Reviewers were enthusiastic about this well-crafted but complex proposal. Reviewers agreed that the scientific rationale for the approach is clear and well-stated. The approach is built upon the applicants’ prior work demonstrating evidence that neural stem cells home to sites of neuropathology, including tumors and specifically GBM. The significance of this proposal is substantial, as patients with GBM have a uniformly poor prognosis with the use of conventional therapies. Any therapy with increased efficacy and lower toxicity would offer a great advance in this field, and would be clinically competitive. Finally, reviewers agreed that this patient group represents one where extraordinary risks are justified and novel therapies appropriate to test.
Reviewers noted that the application included significant preliminary data, including evidence of tumor tropism (in both primary and metastatic brain tumor models), and preliminary efficacy of TRAIL in GBM murine models using a different viral vector. Reviewers noted that the efficacy data could be strengthened by including a second control group of hNSCs not expressing TRAIL. Reviewers expressed complete confidence in this team ability to capture appropriate outcomes since they have demonstrated in many prior studies the ability to study homing, histochemical profiles, and signaling pathways responsible for migration of cells to normal brain and brain tumors in xenograft models. The presence of established preclinical models, established genetic constructs, readout systems, and imaging capabilities increased the panel’s confidence that the plan was achievable.
Reviewers judged the plan to be logical, with ambitious but appropriate milestones and clear go / no go decision criteria. The applicants propose to first select the best cell type based on homing characteristics and ability to deliver the payload to the target, and then proceed to three in vivo models to test for efficacy. Additional strengths include plans to pre-treat the preclinical animals with standard-of-care chemotherapy and radiation, screen for resistance to the cytotoxic agents by testing multiple human GBM samples in the xenogenic model, and include experimental arms with and without cyclosporine immunosuppression. Minor criticisms were leveled against the research plan. The applicant should plan to interact with the FDA in pre IND meetings, and develop a more detailed approach to IND-enabling studies. One reviewer commented that the candidate selection criteria for the cell line were not clearly stated in the application. Another reviewer felt that comparisons to cell-free delivery should be done much earlier in the project, since tropism of hNSCs is the main premise in one arm of the project. Timelines were felt to be perhaps overly ambitious, but again the group’s expertise and prior work with the key technologies reassured reviewers that the plan was feasible overall.
Reviewers unanimously judged the PI and the research team leadership to be a major strength of the proposal, stating that this team is uniquely qualified to achieve the objectives of the proposal. The PI and team leaders are pioneers and leaders in their respective fields. The team brings together experts in tumor suppressor genes and cancer genetics, as well as experts in neural cell biology and a leading researcher in viral vectors. The application contains many examples of the long-standing collaborations that exist among team members. Collaborations bring together five major institutions, and the available resources and institutional commitment are excellent.
In summary, the proposal constitutes a multifaceted effort to develop an allogeneic stem cell product to treat GBM brain tumors. Strengths of the proposal include an extraordinarily qualified collaborative team, a logical plan, significant preliminary data, and strong consideration of the clinical setting. Although the timeline is ambitious and a few minor weaknesses were noted in the plan, reviewers were confident that this is the team that can achieve an IND filing within the 4-year timeframe.
PROGRAMMATIC REVIEW
A motion was made to move this proposal to Tier 1, Recommended for Funding. The panel noted that this application addresses a hopeless disease in which new therapies are desperately needed. The motion carried.